Since nitrogen-containing heterocycles are ubiquitous features of biologically active molecules, new methods for their construction greatly assist scientists working in the fields of medicinal chemistry, drug design, biochemistry, and pharmacology. Lactams are particularly useful because the nitrogen atom is not basic and the functional group is relatively inert to many reaction conditions, yet can be appropriately transformed into amines under appropriate conditions. Accordingly, the purpose of this work is to develop a valuable new reaction that permits ready access to a wide variety of lactams: the acid-catalyzed reaction of alkyl azides and ketones. Although a related process, the Schmidt reaction of hydrazoic acid and ketones, is a well-established tool in heterocyclic chemistry, attempts to extend its scope to include alkyl azides have historically met with failure. However, work in this laboratory over the last year has shown that alkyl azides can in fact react with ketones to afford the corresponding ring-expanded lactams in high yield. Importantly, this permits the conceptualization of an intramolecular process between ketones and azides. The first section details the exploration of the effects of the ketone and azide structure on the intramolecular version of the reaction, considering such variables as tether length, functional group compatibility, stereochemistry, and migratory aptitudes. In addition, aldehydes, thioketones, acetals and ketals, and enol ethers can in principle give intermediates that could react in analogous ways and expand the range of the keto/azide reaction. Finally, although the primary focus of this project will be the development of the synthetic method, some mechanistic work is warranted and will be pursued. The second section of the proposal will outline efforts toward applying these new reactions to the total syntheses of biologically relevant compounds. The targets will be chosen in large part based on opportunities they provide for testing particular aspects of the chemistry central to this proposal. In so doing, a balance is sought between maximizing the types of nitrogen-containing ring systems obtainable by this approach, target complexity, and the importance of analogs of the prototypical targets to biomedical research. The specific compounds suggested for synthesis are: alkaloids A209B and analogs, cavelina pictine alkaloids, lasubine I and/or II, sparteine, 3-demethoxyerythratidinone, lycorane, elwesine, aspidospermine, and cephalotaxine.